DESCRIPTION: (Applicant's Abstract) The abuse of psychomotor stimulants such as cocaine involves the responses of postsynaptic neurons in the striatum to facilitated dopaminergic transmission by these drugs. Diverse evidence implicates specifically the lateral striatum in stereotyped behavior (e.g., licking, head bobbing in rats) induced by high doses of stimulants. The specificity of anatomical locus for this drug effect almost certainly involves our recent discovery that neurons in the lateral, but not medial, striatum of the rat fire in relation to sensorimotor activity of specific body parts. These include large populations of neurons related specifically to head movement or to oral behavior such as licking. However, it is unknown how the activity of these neurons participates in mediating stimulant-induced head bobbing and oral stereotypy, respectively. We have recently begun to address this issue by recording the firing of lateral striatal neurons related to head movement or licking during these movements after saline injection (control) and after stimulant drug injection, while the drug was influencing these movements. A remarkably consistent finding in three separate studies was that the drug effect on firing was firing rate-dependent. That is, after injection, firing rates were elevated during movements normally associated with low firing rates, but were less elevated during movements normally associated with high firing rates (of the same neuron). At high doses, normally high firing rates were strongly suppressed. Thus, even while the drug elevated low rates, inducing movements, it severely restricted the range of striatal firing rates that could be expressed in the presence of the high dose. This may account for the well documented restriction of behavioral diversity in motor behavior (i.e., focused stereotypy) induced by high doses of stimulant drugs. In Specific Aim 1, we will conduct a follow-up experiment to provide an important control for the effect of time, because the above drug effects were always obtained in the second hour, after a saline control had been obtained in the first hour. A group of animals will receive saline in the first hour and saline in the second hour. This is necessary (even though the above effects were dose-dependent) to show that the effects were attributable to the drug and not the passage of time. In Specific Aim 2, we propose to examine the effects of repeated exposure to cocaine. We will assess, as above, drug effects on firing within-session, but also assess whether those effects change across repeated daily sessions. Any changes in drug effects on firing will be examined in relation to changes in the detailed measures we obtain of motor behaviors with which firing is correlated, i.e., head movement or licking. Clarifying stimulant effects on the firing of striatal neurons related to stereotyped movements, and any changes after repeated drug exposure that may accompany sensitization of those movements, can provide novel insights regarding the response of dopamine sensitive neurons to these drugs, which may pertain to their abuse.